Manufacture of hollow fine tubular drug delivery systems

ABSTRACT

Pharmaceutical compositions are provided which contain hollow fine tube drug delivery systems. The compositions comprise a pharmaceutically suitable carrier, preferably in the form of a capsule, tablet, suspension, or suppository, and at least one drug delivery system which consists essentially of (1) a polymeric tube having a membrane outer sheath and a hollow core, and (2) at least one drug compound contained within the core, said system contained in the composition in an amount sufficient to deliver a therapeutic amount of the drug contained therein at a predetermined rate over a predetermined period of time. By varying the polymer, the permeability of the outer sheath, the drug, the drug concentration in the hollow core of the tube, the tube diameter, the tube length, the tube core diameter, and the sealing of the tube ends, a wide variety of drug therapeutic amounts, rates and dosing times can be achieved.

RELATIONSHIP TO OTHER APPLICATIONS

This application is a continuation-in-part of copending U.S. ApplicationSer. No. 730,064, filed May 3, 1985, now U.S. Pat. No. 4,673,565.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to pharmaceutical compositions and moreparticularly to controlled release pharmaceutical compositionscontaining hollow tube drug delivery systems.

2. Prior Art:

Controlled delivery or sustained release formulations have gained widepopularity in the pharmaceutical industry. The popularity of theseformulations has grown due to the usefulness in extending the utility ofparticular drugs which require specific dosages and delivery of thedosage at a non-toxicological rate.

In the pharmaceutical industry, sustained release has been usedextensively for oral medications over a number of years. Sustainedrelease formulations include encapsulated pellets or beads, entericcoated formulations, use of slightly soluble salts, drug complexes, andporous tablets containing dispersed drugs.

Controlled drug delivery on the other hand is aimed at achievingsustained release of a drug at a constant rate (zero order) for longperiods of time. Zero order release can be provided at the present timeonly by mechanical pumps, such as automatic syringes and implantablepumps, osmotic pumps such as Alza's systems known as Alzet®,Progestasert® and Ocusert®, chemically controlled biodegradablemechanisms, and diffusional systems based on polymeric membranes andmatrices such as the currently marketed transdermal systems for thedelivery of nitroglycerin for angina pectoris and scopolamine for motionsickness.

Solid fibers have been used in sutures encapsulated with antibiotics andin intrauterine devices to release hormones.

While much work has been done over many years relating to the sustainedrelease and the controlled release of drugs, there still is a need fornew systems that are capable of delivering a predetermined amount of adrug at a predetermined rate, over a selected time. The presentinvention provides such systems.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a procedure for preparing hollow tubeshaving drugs incorporated in the cores of the tubes via solutions of thedrugs.

FIGS. 2 and 3 illustrate procedures involving membrane formation byutilization of density gradients. If the bath density is less than thetube, the tube will sink and collect at the bottom of the bath (FIG. 2).If the bath density is greater, the spinning device is inverted and thetube will float upward and collect at the top of the phase inversionstage (FIG. 3).

SUMMARY OF THE INVENTION

According to the present invention there is provided a process forpreparing a hollow tube drug delivery system comprising:

a. extruding a polymer solution or suspension through an annular orificeto provide a tubular membrane having a hollow core;

b. simultaneously extruding a drug suspended in a polymer solution intothe hollow core of the tubular membrane to provide a drug encapsulatedtubular membrane system;

c. passing the system into a non-solvent for the polymers having adensity different from that of the system, to coagulate the polymersunder conditions to minimize orientation in the tube polymer and tocreate pores in the tube polymer wall;

d. removing residual solvent from the system; and

e. collecting a drug encapsulated, porous polymeric hollow tube.

According to a preferred embodiment, a plurality of hollow, porous,segmented polyurethane/urea tubes up to 15 cm in length, preferablyabout 0.5 mm to about 2 cm, containing at least one drug in the core aremixed with a suitable pharmaceutical carrier for oral administration.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of hollow tubes from polymers can be achieved by variousroutes. These are referred to as wet, dry or melt-forming processes.Melt-forming involves heating a polymer above its melting point andextruding it through an orifice (usually referred to as a die) which isdesigned to form a hollow tube. Once extruded, the melt is cooled via aquench which allows the polymer to solidify into a fine tube. In thedry-forming process, a solution of the polymer is extruded through adesired orifice and is fed into a heated column which allows forevaporation of the solvent and subsequent formation of a tube. In awet-membrane forming process, a solution of the polymer is extrudedthough an orifice and quenched in a non-solvent for the polymerresulting in coagulation of the polymer to a tube. Of the abovementioned forming processes, wet-membrane forming allows one to easilyproduce hollow porous tubes. It will be appreciated that the particularforming process used will be dependent upon the polymer used and type ofhollow tube desired.

To make a membrane outer sheath in a hollow tube, one first dissolves ordisperses a polymer to form a liquid solution. A porous membrane resultswhen the latter process is reversed under controlled condition. Thepolymer coagulates into a continuous matrix as it separates from thesolvent which forms a dispersion of droplets. As the polymer solidifiesand the solvent is extracted, the dispersion of droplets becomes anetwork of open pores. This phase inversion or separation can beachieved by a number of techniques. In one, the temperature of thepolymer solvent dictates the point at which the phase inversion occurs.In another, the polymer solvent is physically exchanged with a poorsolvent for the polymer causing phase inversion.

The size of the pores is affected by the solvent strength of a polymer.A rapid decrease in solvent strength often tends to entrap a dispersionof small droplets within the continuous polymer phase. A slow decreasein solvent strength allows for nucleation sites within the polymermatrix allowing for formation of larger pores. In this case, thereduction in solvent strength must be rapid enough to allow for thestructure of the membrane to set.

Another way to change porosity and volume of the porous network in thepolymer is to change the concentration of the polymer solution. Lowerconcentrations have a tendency to promote larger pores and greater porevolume. However, there is a limit to how high (usually no more than 45%w/w) the polymer concentration can be in a solvent, otherwise, thepolymer will become the dispersed phase in a continuous solvent phase,thereby eliminating the porous network. Another method to achieve poroustubular membranes is to cause a rapid phase inversion of the polymersolution by cooling.

Generally, as the polymer membrane of the hollow tube is quenched, thesurface of the polymer tends to have a "dense" skin due to a rapidreduction of solvent strength at the surface. The interior, on the otherhand, must have the solvent diffuse and migrate through the polymermatrix. This results in larger interior pores. In a thermally inducedquench, the relative cooling rates can determine the relative degree ofporosity.

Conventional machinery used in the manufacture of tubes often has atendency to orient the polymer by either the mechanical features of thedevice or by the influence of gravity. This often results in distortionof pore shape and orientation in tubular membrane production and alsorequires that the solution have inherent physical properties enabling itto be processed on the conventional equipment. Hot and cold drawing canalso be used to vary the outside diameter of the tube and its corevolume. For example, a large diameter tube can be extruded and thendrawn down to a small diameter.

In order to minimize the effects of orientation and maximize thebenefits of uniform porosity and allow for production of membranes fromfragile polymer systems, a preferred tube forming process called densitygradient membrane formation is used. This process uses density gradientsin the phase inversion bath. Careful selection of the coagulationsolutions allows one to use gravity to gently draw and collect the thintubular membrane in the phase inversion bath. The density gradient ofthe coagulation solution can be established by either multiple stackedlayers of liquids with different densities, or by the use of a singlecoagulant subjected to a temperature gradient which in turn produces adensity gradient. Proper selection of the coagulation solution isextremely important when processing delicate membranes. Depending on thedensity of the tube vs. the quench bath, it can be spun either upwardsor downwards. For drug encapsulation, selection of the quench media isdependent on the drug solubility and miscibility of the solvent for thepolymer.

In order to encapsulate a drug compound in the core of the hollow tube,either a suspension, solution, or other extrudable form of the compoundhas to be prepared initially. This is achieved by selecting a solventfor the drug and dissolving it to a desired concentration or by meltingthe drug material to be encapsulated. Alternatively, a suspension offine particles of drug in an appropriate liquid medium is prepared whichcan either be heated to form a liquid suspension that can be solidifiedin the core of the tube or can be made viscous enough for the drug toremain in suspension. Often a dilute solution of the polymer used tomake the tubular membrane outer sheath serves as an adequate suspendingmedium for the drug. Once the appropriate drug solution or suspension ismade, it is pumped into the annular die simultaneously with the solutionof the polymer forming the outer sheath of the hollow tube. This isschematically illustrated in FIG. 1. The resulting hollow tubecontaining the drug is quenched in an appropriate poor solvent for thepolymer and the drug and is permitted to set in the quench bath. Ifnecessary, the tube can be removed from the initial quench and placed inanother solvent which can expedite removal of the remaining solvent inthe tube, without removing the drug. For example, a volatile non-solventfor the drug and tube can be used to exchange with any residual solventremaining in the tube and subsequently be removed by vacuum extraction.

After the drug encapsulated hollow tube is formed, the continuous tubeis cut into lengths suitable for formulation into a pharmaceuticalcomposition for administration to mammals, particularly in the form of atablet, capsule, suppository, suspension, or suture. The length of thehollow tube can be as long as can conveniently be formulated into adosage form commensurate with the delivery of a therapeutic amount ofthe encapsulated drug. Formulations can be prepared making use ofcarriers, vehicles, diluents, excipients, and procedures well known tothose skilled in the pharmacy art.

For example, the hollow tubular delivery system can be one continuouslength that can be "balled up" into a dosage form. The continuous tubemay be more suitable for the slow release of a drug over a long periodof time via an osmotic pump delivery system. In this delivery system, atleast one of the tube ends is open and the membrane outer sheath isimpermeable to water and the drug, i.e., the drug is delivered out theend of the tube. Release rates can be increased by making the membraneouter sheath permeable or semi-permeable.

Preferred pharmaceutical compositions contain a plurality of drugencapsulated hollow tubes. These tubes can be of uniform length or ofdifferent lengths with the ends either open or sealed. By varying thelengths of the tubes, openness of the ends, and permeability of themembrane outer sheath, the rate and time of delivery can be varied andbe predetermined. Tube lengths up to 15 cm are preferred; however,shorter lengths are more preferred, e.g., the tubes are preferably lessthan 2 cm long, preferably in the range of less than about 0.5 mm toabout 2 cm, and most preferably in the range of about 0.5 mm to about 6mm. The tubes can have both ends open, both ends sealed, or one end openand one end sealed.

The hollow tubes preferably have a small diameter for ease offormulation. While final diameters can be as high as 5 mm, it ispreferred that they be about 0.5 mm in outside diameter or less. Largerdiameter tubes can be spun and then drawn down to a smaller diameter.Aspect ratios (ratio of length to diameter) of the tubes will generallybe in the range of about 1 to 30. The core diameters of the hollow tubestypically range from about 25-90% of the outside diameter, preferablyabout 40-85%.

The drug concentration in the core of the tube depends upon manyvariables and will be loaded to provide the best delivery rate and timespan for the particular drug involved. Drug concentration can vary overa wide range, i.e., about 1-90% by weight of the total weight of thetube and compound; however, it is preferred that the drug concentrationbe in the range of about 5-75% by weight.

The drug in the core can be mixed with a pharmaceutically suitable saltor sugar to increase the dissolution of the drug in the core. This isparticularly appropriate where the tube acts as an osmotic pump sincethe salt or sugar assists in forcing water into the core. Whilemagnesium sulfate is a preferred salt, other useful salts are anywater-soluble, divalent or monovalent salts.

A hollow tube that has been found particularly suitable forpharmaceutical formulations is a segmented polyurethane/urea tube freeof additives having an outside diameter of less than 0.5 to about 1.5mm, a core volume of about 60-90%, a length of about 3-6 mm and a drugconcentration in the range of about 25-75% by weight. The membrane outersheath of these tubes is porous, and had a porosity of 500 daltons ormore, determined by dye penetration tests.

The material of choice for production of the hollow tube depends on thecharacteristics one would like to have in the final product. They can bechosen for ease of membrane fabrication, hydrophilicity, elasticity,molecular weight, biocompatibility, degree of porosity, processingtemperature, and compatibility with the drug being encapsulated.Polymers which can be used include polyolefins such as polypropylene,polyurethanes such as segmented polyurethane/ureas, ethylene-vinylacetate copolymers having a vinyl acetate content of at least 33% byweight, polyvinyl alcohols, and blends of water-soluble polymers withsome of the aforementioned polymers.

Polypropylene can be used for the production of fine hollow tubularmembranes with wide variations in porosity. They are normally meltformed at temperatures above 200° C. but they can also be dissolved insolvents at elevated temperatures and then quenched. Because of the hightemperatures necessary for the fabrication of polypropylene hollowtubes, care must be used in selecting drugs which are not heatsensitive. Alternatively, the drug can be injected into the core of thehollow tube after it is formed; however, such a procedure is notpreferred.

Polyurethanes, such as segmented polyurethane/ureas sold under the nameLycra®, can be dissolved at ambient temperature in dimethylacetamide(DMAC) or other appropriate solvent and fabricated into porous, hollowtubes at ambient temperature. They can also be blended easily withwater-soluble materials such as polyvinylpyrrolidone (PVP), polyethyleneglycol (PEG), and salts which enhance porosity and wettability of theresulting tubular membranes. These tubes have high elasticity, arebiocompatible, and offer great flexibility in the design of hollowtubular membranes, especially by the preferred density gradient membraneformation technique. Copolymers of ethylene-vinyl acetate with at least33% by weight of vinyl acetate can be dissolved at ambient temperaturein tetrahydrofuran (THF) and fabricated into porous hollow tubes. Theyare easily blended with water soluble materials such as PVP, PEG, andsalts. These tubular membrane systems are somewhat elastic, arebiocompatible, and are easily formed into hollow tubes. Hytrel®, apolyester elastomer, can also be formed into porous tubular membranesand blended with water-soluble polymers.

Polyvinyl alcohols can be dissolved easily in hot water at 60° C. andcan be fabricated into porous hollow tubes at ambient temperatures.Because of their solubility in water, they can be used as slowlyerodible matrixes for delivery of active ingredients.

Any therapeutically active drug compound can be used. In the exampleswhich follow, the following compounds were chosen as models because oftheir broad range of chemical and pharmacological characteristics:

Phenylpropanolamine hydrochloride, a decongestant, pKa (base)=9.5, isfreely soluble in water (25° C.).

Theophylline, an antiasthma drug, pKa (base)=0.36 with a solubility inwater of 1 gram in 120 mls (25° C.).

Chlorpheniramine maleate, an antihistamine, pKa (base)=8.99, has asolubility of 1 gram in 3.4 ml water (25° C.).

Salicylic acid, a topical antiseptic, pKa=2.97, is slightly soluble inwater.

Indomethacin, an antiinflammatory drug, pKa (acid)=4.5, has a lowsolubility in water.

Nalbuphine hydrochloride, an analgesic, pKa (base)=8.4, is soluble inwater.

In the Examples which follow, hollow tubes were prepared by one of twoprocedures which can be varied depending upon the end results desired.Drugs were incorporated in the cores of the tubes via solutions orsuspensions of the drugs.

PROCEDURE A

This procedure uses the arrangement shown in FIG. 1. In this procedure,a solution of the polymer for the outer membrane sheath is pumpedthrough the annular die simultaneously with a solution of the corematerial which results in a tubular membrane surrounding core solution.This is passed through an annular die (O.D.=2.18 mm) into a quench tubecontaining 1 liter of a coagulant for the polymer. The solvent iscontinuously removed from the polymer/drug encapsulated system and it iscollected in a rotating piddle pot. The loaded tube remains in thepiddle pot as the solvent is being removed and is removed after solventremoval is nearly complete for further treatment, e.g., removal of traceamounts of solvent. The tube is formed at a rate of 0.1 to 2 cm³ /minand the speed of the piddle pot is the same as the speed of the tube asit exits the quench tube. Temperature of spinning and coagulation arecontrolled by heating mantles surrounding the die and coagulationkettle.

Table I gives Examples of drug loaded tubes which were formed by theabove method. All runs were conducted at room temperature.

PROCEDURE B

This procedure involves membrane formation by utilization of densitygradients. This procedure is desirable for most applications wheremembrane fabrication and drug encapsulation are involved. Due toexcessive "draw" which is inherent in most extrusion techniques and alsoto the difficulty of fabricating slow forming membranes or tubes whosepolymer structure has weak physical characteristics, this procedureallows for membrane formation of polymers having any or all of thecharacteristics mentioned. By correctly choosing coagulants with adensity slightly different than that of the polymer/drug encapsulatedtube, one can use gravity to gently draw and collect a forming tubewithin the phase inversion bath (coagulant). If the bath density is lessthan the tube, the tube will sink and collect at the bottom of the bath(FIG. 2). If the bath density is greater, the spinning device isinverted and the tube will float upward and collect at the top of thephase inversion stage (FIG. 3). This procedure can use several bathfluids of decreasing density stacked vertically in the tube allowing forflexibility in design to give the ability to use a sequence ofquench-coagulation treatments in the same phase inversion unit. Forexample, a layer of a heavy liquid can be placed adjacent to the die forthermal insulation. A lighter heat conductive liquid on top of thislayer becomes the quenching agent.

The encapsulation of drugs is accomplished by dissolving or suspendingthe drug in a suitable liquid, or melting the drug, then taking thisdrug preparation and loading it into a stainless steel piston used forinserting the core material. A second piston for the outer sheathmembrane contains the polymer solution. Temperature control, ifnecessary, of the pistons, die, and coagulant is accomplished by heatingjackets. Die size is chosen depending on the diameter of the tubedesired, and on the lumen desired. The rate at which the polymer anddrug is pumped is controlled by settings on the pumps. The gap betweenthe die and the top of the coagulation bath, where appropriate, is setaccording to the amount of "draw down" desired. This procedure is morefully described by the following:

The porous, polymeric hollow tube is formed by extruding a tubularmembrane from a polymer solution or suspension and then passing thetubular membrane into a coagulation bath which is a non-solvent for thepolymer. Simultaneously with the extrusion of the hollow tube, a drugsuspension (drug suspended in a polymer solution) is extruded at thesame rate as the tube extrusion into the hollow core of the tubularmembrane to form a drug encapsulated tubular membrane system. In thecoagulation bath the solvent is removed from the system via phaseinversion, during which the pores in the polymer wall are formed. Afterremoval from the coagulation bath, residual solvent is removed, and thedrug encapsulated, porous, polymeric hollow tube is collected, e.g., ona take-up roll. From the take-up roll, the collected drug-filled tube iscut into desired lengths, ends sealed as desired, and a plurality of thecut tubes are mixed with a suitable pharmaceutical carrier for oraladministration.

The polymer solution which forms the porous, tubular membrane ispreferably a solution of about 15-40% (preferably 30-40%) by weight of asegmented polyurethane/urea derived from polyether soft segments(Lycra®) and free of additives and dissolved in dimethylacetamide (DMAC)or N-methylpyrrolidone (NMP), preferably DMAC. Another useful polymersolution is a solution of about 15-25% by weight of a polylactide havinga number average molecular weight of about 100,000 to 500,000 in NMP,DMAC or a chlorinated solvent such as chloroform, or methylene chloride.The polylactide can be formed from polymerization of lactic acid. Afurther useful polymer solution is a solution of about 15-25% by weightof polyvinyl alcohol in water. The polyvinyl alcohol is a homopolymerwhich is a fully hydrolyzed polyvinyl acetate (with about greater than99.8% of the acetate groups converted to alcohol groups) or a partiallyhydrolyzed polyvinyl acetate with up to about 25% of residual vinylacetate groups. In addition, the polyvinyl alcohol can be a copolymerwith an acrylic monomer such as methyl acrylate.

While the above polymers are preferred, any polymer can be used that issoluble in water or an organic solvent up to a concentration in thesolvent of about 40% by weight. Other such polymers includeethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose,ethylene/vinyl acetate, and cellulose acetate.

The drug suspension extruded into the hollow core of the tubularmembrane can be a suspension of any drug in a polymer solution eitherthe same as or different from the polymer solution used to prepare thehollow tubular membrane. Drugs are usually solids and a solid drug inpowder form is preferred. Preferred polymer solutions are propyleneglycol, polyethylene glycol having a molecular weight greater than 400(preferably in the range of about 400-5000), about 1-12% by weight of asegmented polyurethane/urea derived from polyether soft segments, andabout 1-5% by weight of polyvinyl alcohol in water. Other polymersolutions can be used such as sodium carboxymethylcellulose,hydroxypropyl cellulose, and hydroxypropylmethyl cellulose. Typically,the drug will comprise about 3-50% by weight in the polymer solution.

The coagulation bath for the extruded system is composed of anon-solvent for the polymer used for the tubular membrane. This ispreferably water, an alkyl alcohol of 1-3 carbon atoms (preferablymethanol or ethanol, or a mixture of the two). Other useful non-solventsare acetone, ether, and aqueous solutions of sodium sulfate, or sodiumhydroxide. As stated earlier, the density of the non-solvent isdifferent from the extruded system so that the system either rises tothe top of the bath or, as preferred, sinks slowly to the bottom of thebath prior to removal and collection. A small difference in densitiesminimizes orientation in the tubular polymer wall and allows thecreation of uniform pores in the tube wall during phase inversion.

The temperatures for extrusion and for the coagulation bath arepreferably about the same but can be different depending upon theproperties desired in the final product. Preferred temperatures areabout room temperature; however, the temperature for the extrusions andfor the coagulation bath can be independently in the range of about 15°to 180° C., depending on the heat stability of the polymer. To increasethe pore size in the tubular polymer wall, the temperature can beincreased to the high end, i.e., in the range of about 60° to 180° C.

Slight draw-down can be made in the extruded system to narrow theoutside diameter of the final product. This is accomplished by drivingthe take-up roll, when extruding upward, at a slight higher speed as iswell-known in the art. In the preferred downward extrusion, an airgap isprovided between the die and the bath so as to give a slight neck-in.This gap can vary between 0 and a few inches, depending on theproperties desired in the final product.

After removal from the coagulation bath, residual solvent is removedfrom the drug encapsulated, porous, polymeric hollow tube preferably byheat or by passing the product through a vacuum. The final product,having an outside diameter of about 0.5-10 millimeters, preferably about0.5-5 millimeters is collected for subsequent processing and use.

In Tables I and II are given the conditions and characteristics of thetubes prepared using this procedure. All parts and percentages are byweight.

The following abbreviations are used in the tables:

    ______________________________________                                        Polymers and solvents:                                                        Ur126 =      Segmented polyurethane/urea                                                   (50,000 molecular weight)                                        PVP-15 =     Polyvinylpyrrolidone (15,000                                                  molecular weight; 40 = 40,000                                                 molecular weight)                                                PEG =        Polyethylene glycol (400 molecular                                            weight; 740 molecular weight; 1000                                            molecular weight; 1300 molecular                                              weight; 3350 molecular weight)                                   PG =         Propylene glycol                                                 EVA =        Copolymer of ethylene-vinyl                                                   acetate with 33% by weight vinyl-                                             acetate (melt index 43, density                                               0.95 g/cc)                                                       NMP =        1-Methyl-2-pyrrolidone                                           DMAC =       Dimethylacetamide                                                THF =        Tetrahydrofuran                                                  Dowex =      Dowex 50 cross-linked sulfonated                                              polystyrene ion exchange resin                                   Drugs                                                                         Sal. Acid =  Salicylic acid                                                   PPA =        Phenylpropanolamine hydrochloride                                CM =         Chlorpheniramine Maleate                                         Nalb--HCl =  Nalbuphine hydrochloride                                         Theo =       Theophylline                                                     Ind =        Indomethacin                                                     ______________________________________                                    

                                      TABLE I                                     __________________________________________________________________________    Hollow Thin Tubular Membrane                                                  Preparation With Encapsulated Drugs                                                                          Direction                                                     Core %          of                                             Ex.                                                                              Polymer     in Susp.   Airgap                                                                             Membrane                                       No.                                                                              (Solvent)   or Soln.   (Inches)                                                                           Formation                                                                           Quench                                   __________________________________________________________________________     1 36% Ur126 (DMAC)                                                                          3% Theo in PG                                                                            0    A     H.sub.2 O                                 2 36% Ur126 (DMAC)                                                                          10% Sal. Acid                                                                            0    A     H.sub.2 O                                               in PG                                                           3 36% Ur126 (DMAC)                                                                          3% Theo in PG                                                                            0    A     H.sub.2 O                                 4 36% Ur126 (DMAC)                                                                          30% Sal. Acid                                                                            0    A     H.sub.2 O                                               in PEG 740                                                      5 36% Ur126 (DMAC)                                                                          30% Sal. Acid                                                                            0    A     H.sub.2 O                                               in PEG 1000                                                     6 36% Ur126 (DMAC)                                                                          30% Sal. Acid                                                                            0    A     H.sub.2 O                                               in PEG 1300                                                     7 36% Ur126 (DMAC)                                                                          25% Ind. in                                                                              1    B(down)                                                                             60%                                                     PEG 3350              Ethanol                                                                       in H.sub.2 O                              8 36% Ur126 (DMAC)                                                                          50% Nalb--HCl in                                                                         1/4  B(down)                                                                             60%                                                     3.6% Ur (DMAC)        Ethanol                                                                       in H.sub.2 O                              9 36% Ur126 (DMAC)                                                                          50% Nalb--HCl in                                                                         1/4  B(down)                                                                             60%                                                     3.6% Ur (DMAC)        Ethanol                                                                       in H.sub.2 O                             10 36% Ur126 with                                                                            25% Nalb--HCl in                                                                         1/4  B(down)                                                                             60%                                         15% PVP40 (DMAC)                                                                          1.8% Ur126 in         Ethanol                                                 DMAC                  in H.sub.2 O                             11 36% (Ur126 +                                                                              25% Nalb--HCl in                                                                         1/4  B(down)                                                                             60%                                         25% PVP-15)(DMAC)                                                                         1.8% Ur126 in         Ethanol                                                 DMAC                  in H.sub.2 O                             12 36% Ur126 (DMAC)                                                                          25% Nalb--HCl in                                                                         1/4  B(down)                                                                             60%                                                     1.8% Ur126 in         Ethanol                                                 DMAC                  in H.sub.2 O                             13 15% Elvanol 50% PPA in 0    B(down)                                                                             60%                                         HV (H.sub.2 O)                                                                            2% Elvanol in         Ethanol                                                 H.sub.2 O             in H.sub.2 O                             14 20% EVA 150 (THF)                                                                         25% Theo in                                                                              1/2  B(down)                                                                             60%                                                     3.6% Ur126 (DMAC)     Ethanol                                                                       in H.sub.2 O                             15 36% (Ur126 +                                                                              25% Theo in                                                                              0    B(down)                                                                             60%                                         25% PVP-15)(DMAC)                                                                         3.6% Ur126 (DMAC)     Ethanol                                                                       in H.sub.2 O                             16 Polypropylene                                                                             33% Theo   Not spun (encapsulated                                             325 mesh in 3.6%                                                                         in previously prepared                                             Ur126 (DMAC)                                                                             tube                                                17 36% Ur126   50% CM in  1    B(down)                                                                             80%                                                     3.6% Ur126 (DMAC)     Acetone                                                                       in H.sub.2 O                             18 36% (Ur126: 33% (PPA-Dowex)                                                                          0    B(up) Deionized                                   PVP-15,1:1) in 3.6% Ur126         Distilled                                               (DMAC)                Water                                    __________________________________________________________________________     A = Quench tube and rotating piddle bucket (coagulant flows in direction      spun)                                                                         B = Quench tube bath (stationary)                                        

In vitro dissolution rates of drug-filled hollow tubes whose preparationis shown in Table I were carried out by one of two procedures. One is astandard procedure described in the U.S. Pharmacopeia XXI, page 1243(1985). This procedure uses a 1 liter glass vessel immersed in water at30° C. or 37° C. and filled with a specified amount of drug encapsulatedtubes and an appropriate dissolution medium (0.1N HCl, pH 7.4 phosphatebuffer, buffered saline or water). This vessel is stirred at a constantrate (25, 50 or 100 rpm) for the duration of the dissolution procedureand its contents are sampled periodically to determine the amount ofdrug released.

The second procedure, sometimes referred to as the rotating bottlemethod, uses sealed, cylindrical glass tubes immersed in water at 30° C.or 37° C. and filled with drug encapsulated tubes and an appropriatedissolution medium as described above. The glass tubes are tumbled at aspecified rate (15 rpm) throughout the test and the contents are sampledperiodically to determine the amount of drug released. The length of thetests vary depending on the rate of release of the drug (2-100 hours).Time should be long enough to allow significant (˜>50%) release of drug.

The in vitro dissolution procedures of Table I hollow tubes are shown inTable II along with the characteristics of the tubes. The dissolutionresults are discussed after Table II.

                                      TABLE II                                    __________________________________________________________________________    Drug-encapsulated Thin Tubular                                                Membranes And Dissolution Rates                                                                    Tube      Drug                                              Mem- Drug &       Dia.      Loading                                        Ex.                                                                              brane                                                                              Susp.  Tube  (OD       Ult. %                                                                             Dissol.                                   No.                                                                              Sheath                                                                             Agent  Length                                                                              mm.)                                                                             Char.  of Total                                                                           Proc.                                     __________________________________________________________________________     1 Ur126                                                                              3% Theo.                                                                             1"    1.5                                                                              Closed  2%  USP 30° C./                                in PG  (2.54 cm)                                                                              ends 70%    50 rpm.sup.1                                                      Lumen Dia.                                             2 Ur126                                                                              10% sal.                                                                             1"    1.5                                                                              Closed  6.9%                                                                              USP 30° C./                                acid in                                                                              (2.54 cm)                                                                              ends 70%    50 rpm.sup.1                                      PG              Lumen Dia.                                             3 Ur126                                                                              3% Theo.                                                                             1"    1.5                                                                              Closed  2%  rot. bottle                                       in PG  (2.54 cm)                                                                              ends 60%    37° C./                                                    Lumen Dia.  15 rpm.sup.1                               4 Ur126                                                                              30% sal.                                                                             1"    3.6                                                                              Closed 12%  rot. bottle                                       acid in                                                                              (2.54 cm)                                                                              ends 67%    30° C./                                    PEG 740         Lumen Dia.  15 rpm.sup.1                               5 Ur126                                                                              30% sal.                                                                             1"    3.0                                                                              Closed 22%  rot. bottle                                       acid in                                                                              (2.54 cm)                                                                              ends 33%    30° C./                                    PEG 1000        Lumen Dia.  15 rpm.sup.1                               6 Ur126                                                                              30% sal.                                                                             1"    3.0                                                                              Closed 20.2%                                                                              rot. bottle                                       acid in                                                                              (2.54 cm)                                                                              ends 33%    30° C./                                    PEG 1300        Lumen Dia.  15 rpm.sup.1                               7 Ur126                                                                              25% Ind.                                                                             1"    2.3                                                                              Closed 17%  USP 37° C./                                in PEG (2.54 cm)                                                                              ends 33%    25 rpm.sup.1                                      3350            Lumen Dia.                                             8 Ur126                                                                              50:3.6 1"    1.8                                                                              Closed and                                                                           56%  USP 37° C./                                Nalb--HCl:                                                                           (2.54 cm)                                                                              open 82%    50 rpm.sup.2                                      Ur126           Lumen Dia.                                             9 Ur126                                                                              50:3.6 1/2", 1  Open -50%                                                                            39.8%                                                                              USP 37° C./                                Nalb--HCl:                                                                           1"       Lumen Dia.  50 rpm.sup.2                                      Ur126  (1.27,                                                                        2.54 cm)                                                       10 Ur126                                                                              25:1.8 1"    1  Open and                                                                             40%  USP 37° C./                           & 15%                                                                              Nalb--HCl:                                                                           (2.54 cm)                                                                              closed 50%  50 rpm.sup.2                                 PVP-40                                                                             Ur126           Lumen Dia.                                            11 Ur126                                                                              25:1.8 1"    1  Open and                                                                             56%  USP 37° C./                           & 25%                                                                              Nalb--HCl:                                                                           (2.54 cm)                                                                              closed 67%  50 rpm.sup.2                                 PVP-15                                                                             Ur126           Lumen Dia.                                            12 Ur126                                                                              25:1.8 1"    1  Open and                                                                             66%  USP 37° C./                                Nalb--HCl:                                                                           (2.54 cm)                                                                              closed 74%  50 rpm.sup.2                                      Ur126           Lumen Dia.                                            13 Elvanol                                                                            50:2 PPA:                                                                            1"    0.8                                                                              Closed ends                                                                          28%  USP 37° C./                           HV   Elvanol                                                                              (2.54 cm)                                                                              40% Lumen   100 rpm.sup.2                                     HV                                                                    14 EVA 150                                                                            25:3.6 1"    0.8                                                                              Closed ends                                                                          30%  USP 37° C./                                Theo:Ur126                                                                           (2.54 cm)                                                                              35% Lumen   100 rpm.sup.2                             15 Ur126                                                                              25:3.6 1"    1.2                                                                              Closed ends                                                                          51%  USP 37° C./                           & 25%                                                                              Theo:  (2.54 cm)                                                                              40% Lumen   100 rpm.sup.2                                PVP-15                                                                             Ur126                                                                 16 Poly-                                                                              33:3.6 1"    1.2                                                                              Closed ends                                                                          25%  USP 37° C./                           propyl-                                                                            Theo:  (2.54 cm)                                                                              37% Lumen   100 rpm.sup.2                                ene  Ur126                                                                 17 Ur126                                                                              50:3.6 1/8", 0.9                                                                              Open ends                                                                            28%  USP 37° C./                                CM:Ur126                                                                             1/2"     75% Lumen   100 rpm.sup.2                                            (0.32 cm,                                                                     1.27 cm)                                                       18 1:1  33:3.6 1/8", 0.68                                                                             Open Ends                                                                            57%  USP 37° C./                           Ur126:                                                                             PPA-Dowex                                                                            1/4",    86% Lumen   100 rpm.sup.3                                PVP-15                                                                             Ur126  1/2"                                                                          (0.32, 0.64,                                                                  1.27 cm)                                                       __________________________________________________________________________     .sup.1 0.05 M pH 7.4 phosphate buffer                                         .sup.2 distilled water                                                        .sup.3 0.1 NHCl                                                          

The drug release patterns obtained with the pharmaceutical compositionsof this invention can be further understood by reference to thefollowing examples in which temperatures are in degrees centigrade.

EXAMPLE 1

The dissolution of theophylline from hollow porous polyurethane tubescontaining 2% theophylline by weight was determined in pH 7.4 phosphatebuffer at 30° C. using the USP dissolution procedure. The tubes wereprepared by encapsulating a 3% suspension of theophylline in propyleneglycol in polyurethane 126 tubes prepared to have a 1.5 mm outsidediameter with a 70% lumen diameter. The drug encapsulated tubes were cutin one inch lengths and both ends were closed. The dissolution bath wasstirred at 50 rpm. During the first hour, about 25% of the theophyllinewas released, followed by a sustained release with about 80% of thetotal theophylline being released by 11 hours.

EXAMPLE 2

The dissolution of salicylic acid from hollow porous polyurethane tubescontaining 6.9% salicylic acid by weight was determined in pH 7.4phosphate buffer at 30+ C. using the USP dissolution procedure. Thetubes were prepared by encapsulating a 10% suspension of salicylic acidin propylene glycol in poyurethane 126 tubular membranes prepared tohave a 1.5 mm outside diameter with a 70% lumen diameter. The tubes werecut to one inch lengths and both ends were closed. The dissolution bathwas stirred at 50 rpm. Rapid release of 60% of the salicylic acid wasobserved during the first hour, followed by complete release over 3hours.

EXAMPLE 3

The dissolution of theophylline from hollow porous polyurethane tubescontaining 2% theophylline by weight was determined in pH 7.4 phosphatebuffer at 37° C. using the rotating bottle sustained release apparatusequipped with 50 ml bottles. The tubes were prepared by encapsulating a3% suspension of theophylline in propylene glycol in polyurethane 126tubular membranes prepared to have a 1.5 mm outside diameter with a 60%lumen diameter. The tubes were cut in one inch lengths and both endswere closed. The bottles were tumbled in the constant temperature bathat 10 rpm. During the first 1/2 hour, about 40% of the theophylline wasreleased, followed by more constant release to give complete dissolutionover 4 hours.

EXAMPLE 4

The dissolution of salicylic acid from hollow porous polyurethane tubescontaining 12% salicylic acid by weight was determined in pH 7.4phosphate buffer at 30+ C. using the rotating bottle sustained releaseapparatus equipped with 50 ml bottles. The drug encapsulated tubes wereprepared by encapsulating a 30% suspension of salicylic acid inpolyethylene glycol 740 in polyurethane 126 tubes prepared to have a 3.6mm outside diameter with a 67% lumen diameter. The tubes were cut in oneinch lengths with both ends closed. The bottles were tumbled in theconstant temperature bath at 15 rpm. During the first 1/2 hour, about30% of the salicylic acid was released, followed by more constantrelease of 95% of the total salicylic acid over 6 hours.

EXAMPLE 5

The dissolution of salicylic acid from hollow porous polyurethane tubescontaining 22% salicylic acid by weight was determined in pH 7.4phosphate buffer at 30° C. using the rotating bottle sustained releaseapparatus equipped with 50 ml bottles. The tubes were prepared byencapsulating a 30% suspension of salicylic acid in polyethylene glycol1000 in polyurethane 126 membranes prepared to have a 3.0 mm outsidediameter and a 33% lumen diameter. The tubes were cut in one inchlengths with both ends closed. The bottles were tumbled in the constanttemperature bath at 15 rpm. During the first 1/2 hour, about 35% of thesalicylic acid was released, followed by more constant release of 95% ofthe total salicylic acid over 6 hours.

EXAMPLE 6

The dissolution of salicylic acid from hollow porous polyurethane tubescontaining 20.2% salicylic acid by weight was determined in pH 7.4phosphate buffer at 30° C. using the rotating bottle sustained releaseapparatus equipped with 50 ml bottles. The tubes were prepared byencapsulating a 30% suspension of salicylic acid in polyethylene glycol1300 in polyurethane tubes prepared to have a 3.0 mm outside diameterand a 33% lumen diameter. The drug loaded tubes were cut in one inchlengths with both ends closed. The bottles were tumbled in the constanttemperature bath at 15 rpm. during the first 1/2 hour, about 40% of thesalicylic acid was released, followed by more constant release of 78% ofthe total salicylic acid over 6 hours.

EXAMPLE 7

The dissolution of incomethacin from hollow porous polyurethane tubescontaining 17% indomethacin by weight was determined in pH 7.4 phosphatebuffer using the USP dissolution procedure at 37° C. The tubes wereprepared by encapsulating a 25% suspension of indomethacin inpolyethylene glycol 3350 in polyurethane 126 tubular membranes preparedto have a 2.3 mm outside diameter with a 33% lumen diameter. The drugloaded tubes were cut in one inch lengths with both ends closed. Thedissolution bath was stirred at 25 rpm. During the first 1/2 hour, about42% of the indomethacin was released, followed by more constant releaseof about 85% of the total indomethacin over 11 hours.

EXAMPLE 8

The dissolution of nalbuphine hydrochloride from hollow porouspolyurethane tubes containing 56% nalbuphine hydrochloride by weight wasdetermined in distilled water using the USP dissolution procedure at 37°C. The tubes were prepared by encapsuating a mixture of 50 partsnalbuphine hydrochloride to 3.6 parts polyurethane 126 in polyurethane126 tubular membranes prepared to have a 1.8 mm outside diameter with a82% lumen diameter. The drug encapsulated tubes were cut in one inchlengths with either both ends closed or both ends left open. Thedissolution bath was stirred at 50 rpm. The open-ended tubes showedalmost constant release of nalbuphine hydrochloride with completerelease over 100 hours. The closed-ended tubes showed almost constantrelease of nalbuphine hydrochloride; however, only about 25% of thetotal nalbuphine hydrochloride had been released after 100 hours.

EXAMPLE 9

The dissolution of nalbuphine hydrochloride from hollow porouspolyurethane tubes containing 39.8% nalbuphine hydrochloride by weightwas determined in distilled water using the USP dissolution procedure at37° C. The tubes were prepared by encapsulating a mixture of 50 partsnalbuphine hydrochloride to 3.6 parts polyurethane 126 in polyurethane126 tubes prepared to have a 1 mm outside diameter and a 50% lumendiameter. The tubes were cut in one inch and in 1/2 inch lengths, givingtubular membranes having aspect ratios (length/diameter) of about 25 and12.5 respectively. The ends of the drug encapsulated tubes were leftopen. The dissolution bath was stirred at 50 rpm. Both sets of tubesshowed virtually constant release of nalbuphine hydrochloride with thetubes with an aspect ratio of 25 resulting in release of about 20% ofthe total nalbuphine hydrochloride over a 24 hour period, while thetubes with an aspect ratio of 12.5 resulted in about 65% of the totalnalbuphine hydrochloride being released over a 24 hour period.

EXAMPLE 10

The dissolution of nalbuphine hydrochloride from hollow porouspolyurethane tubes containing 15% polyvinylpyrrolidone and 40%nalbuphine hydrochloride by weight was determined in distilled waterusing the USP dissolution procedure at 37° C. The tubes were prepared byencapsulating a mixture of 25 parts nalbuphine hydrochloride and 1.8parts polyurethane 126 in a tube containing 15% polyvinylpyrrolidone 40in polyurethane 126 prepared to have a 1 mm outside diameter and a 50%lumen diameter. The drug encapsulated tubes were cut to one inch lengthsand the ends were either closed or left open. The dissolution bath wasstirred at 50 rpm. The open-ended tubes showed an initial release ofabout 5% of the nalbuphine hydrochloride during the first 1/2 hour,followed by a sustained release of 40% of the total nalbuphinehydrochloride by 24 hours. The closed-end tubes showed a rapid releaseof about 4.5% of the nalbuphine hydrochloride during the first 2 hours,followed by a more sustained release of 8% of the total nalbuphinehydrochloride by 24 hours.

EXAMPLE 11

The dissolution of nalbuphine hydrochloride from hollow porouspolyurethane tubes containing 25% polyvinylpyrrolidone 15 and 56%nalbuphine hydrochloride by weight was determined in distilled waterusing the USP dissolution procedure at 37° C. The tubes were prepared byencapsulating a mixture of 25 parts nalbuphine hydrochloride to 1.8parts polyurethane 126 in a tube containing 25% polyvinylpyrrolidone 15in polyurethane 126 prepared to have a 1 mm outside diameter and a 67%lumen diameter. The drug encapsulated tube was cut to one inch lengthsand the ends were either closed or left open. The dissolution bath wasstirred at 50 rpm. the open-ended tubes showed a fairly constant releasewith about 36% of the total nalbuphine hydrochloride being released in24 hours. The tubes with the closed ends showed an initial release ofabout 5% of the nalbuphine hydrochloride during the first 1/2 hour,followed by sustained release to reach 10% of the total nalbuphinehydrochloride at 24 hours.

EXAMPLE 12

In contrast to the dissolution observed in Example 11a the dissolutionof nalbuphine hydrochloride from hollow porous tubes of polyurethanealone, rather than the blended polymers used in Example 11, was found tobe much slower. Tubes were prepared which contained 66% nalbuphinehydrochloride by weight by encapsulating a mixture of 25 partsnalbuphine hydrochloride and 1.8 parts polyurethane 126 in polyurethane126 tubes with a 1 mm outside diameter and a 74% lumen diameter. Thedrug encapsulated tubes were cut to one inch lengths and the ends wereeither closed or left open. The dissolution was determined under thesame conditions as those used for Example 11. The open-ended tubesresulted in only 4% dissolution of the total nalbuphine hydrochloride at24 hours, while the closed-ended tubes released only 1.5% of the totalnalbuphine hydrochloride at 24 hours.

EXAMPLE 13

The dissolution of phenylpropanolamine hydrochloride from hollow porousElvanol HV tubes containing 28% phenylpropanolamine hydrochloride byweight was determined in distilled water using the USP dissolutionprocedure at 37° C. The tubes were prepared by encapsulating a mixtureof 50 parts phenylpropanolamine hydrochloride and 2 parts Elvanol HV inan Elvanol HV tube prepared to have an outside diameter of 0.8 mm with a40% lumen diameter. The drug encapsulated tubes were cut to one inchlengths and the ends were closed. The dissolution bath was stirred at100 rpm. Complete release of the phenylpropanolamine hydrochloride wasobserved in the first two hours.

EXAMPLE 14

The dissolution of theophylline from hollow ethylene vinyl acetate tubescontaining 30% theophylline was determined in distilled water using theUSP dissolution procedure at 37° C. The tubes were prepared byencapsulating a mixture containing 25 parts theophylline to 3.6 partspolyurethane 126 in a tubular membrane of ethylene-vinyl acetatecopolymer (33% vinyl acetate by weight) prepared to have an outsidediameter of 0.8 mm and a 35% lumen diameter. The drug encapsulated tubeswere cut to one inch lengths and the ends were closed. The dissolutionbath was stirred at 100 rpm. After an initial release of about 20% ofthe theophylline during the first 1/2 hour, a constant release wasobserved resulting in complete release of the total theophylline by 24hours.

EXAMPLE 15

The dissolution of theophylline from hollow porous polymethane tubescontaining 25% polyvinylpyrrolidone and 51% theophylline by weight wasdetermined in distilled water using the USP dissolution procedure at 37°C. The tubes were prepared by encapsulating a mixture of 25 partstheophylline to 3.6 parts polyurethane 126 in a tubular membrane ofpolyurethane 126 polyvinylpyrrolidone 15 blend (25%polyvinylpyrrolidone) prepared to have an outside diameter of 1.2 mmwith a 40% lumen diameter. The drug encapsulated tubes were cut to oneinch lengths and the ends were closed. The dissolution bath was stirredat 100 rpm. After an initial release of 20% of the theophylline in thefirst 15 minutes a constant release was observed with complete releaseof the theophylline by 24 hours.

EXAMPLE 16

The dissolution of theophylline from hollow polypropylene tubes with amean wall porosity of <0.1 mm containing 25% theophylline by weight wasdetermined in water using the USP dissolution procedure at 37° C. Thetubes were prepared by encapsulating a mixture containing 33 partstheophylline to 3.6 parts polyurethane 126 in polypropylene tubesprepared to have an outside diameter of 1.2 mm and a 37% lumen diameter.The drug encapsulated tubes were cut to one inch lengths and the endswere closed. The dissolution bath was stirred at 100 rpm. After aninitial release of 11% of the theophylline in the first 1/2 hour,sustained release was observed with 80% of the total theophylline beingreleased by 24 hours.

EXAMPLE 17

The release of chlorpheniramine maleate from hollow porous polyurethanetubes containing 28% chlorpheniramine maleate by weight was determinedin distilled water using the USP dissolution procedure at 37° C. Thetubes were prepared by encapsulating a mixture containing 50 partschlorpheniramine maleate to 3.6 parts polyurethane 126 in a polyurethane126 tubular membrane prepared to have an outside diameter of 0.9 mm anda 75% lumen diameter. The drug encapsulated tubes were cut to lengths of1/8 inch (0.32 cm) or 1/2 inch (1.27 cm), giving tubes with an aspectratio of 1.4 or 5.6 respectively and the ends were left open. Thedissolution bath was stirred at 100 rpm. The tubes with an aspect ratioof 1.4 showed an initial release of 22% of the chlorpheniramine maleatein the first 1/2 hour, followed by a sustained release to provide 85% ofthe total chlorpheniramine maleate at 8 hours. The tubes with an aspectratio of 5.6 showed a constant release to provide 23% of the totalchlorpheniramine maleate at 8 hours.

EXAMPLE 18

Release of phenylpropanolamine hydrochloride (PPA) from open-endedhollow tubes whose sheath is constructed of a 1:1 blend of urethane 126and polyvinylpyrrolidone and with aspect ratios of from 4.6, 9.2, and18.6 were performed in 0.1N HCl and compared to that obtained with thecore material. The release pattern for the drug encapsulated tubes wassustained after an initial burst of 2, 3, and 6% (in <1/2 hour) and at24 hours was about 42%, 60% and 70% for the small, medium, and lowaspect ratio tubes respectively. The core component showed a fasterrelease of PPA with a burst of 30% in <1/2 hour up to 100% in 20 hours.

What is claimed is:
 1. A process for preparing a hollow tube drugdelivery system comprising:a. extruding a polymer solution or suspensionthrough an annular orifice to provide a tubular membrane having a hollowcore; b. simultaneously extruding a drug suspended in a polymer solutioninto the hollow core of the tubular membrane to provide a drugencapsulated tubular membrane system; c. passing the system into anon-solvent for the polymers having a density different from that of thesystem, to coagulate the polymers under conditions to minimizeorientation in the tube polymer and to create pores in the tube polymerwall; d. removing residual solvent from the system; and e. collecting adrug encapsulated, porous polymeric hollow tube.
 2. The process of claim1 wherein the drug encapsulated tubular membrane system from step b. isdrawn-down prior to being passed into the non-solvent coagulant.
 3. Theprocess of claim 1 wherein the resulting drug encapsulated, poroushollow tube has an outside diameter of about 0.5-10 millimeters.
 4. Theprocess of claim 3 wherein the collected tube is cut into lengths in therange of about 0.5 mm to about 2 cm.
 5. The process of claim 3 whereinthe polymer solution is about 15-40% by weight of a segmentedpolyurethane (urea derived from polyether glycol soft segments and freeof additives in dimethylacetamide or N-methylpyrrolidone.
 6. The processof claim 5 wherein polymer solution is about 30-40% by weight of thesegmented polyurethane/urea in dimethylacetamide.
 7. The process ofclaim 3 wherein the polymer solution is about 15-25% by weight of apolylactide of number average molecular weight of about 100,000 to500,000 in dimethylacetamide or a chlorinated solvent.
 8. The process ofclaim 7 wherein polylactide is dissolved in chloroform.
 9. The processof claim 3 wherein the polymer solution is about 15-25% by weight ofpolyvinyl alcohol in water.
 10. The process of claim 3 wherein theextrusions of steps a. and b. are downward through an airgap to affectdraw-down by gravity, and the non-solvent coagulant has a density lessthan the density of the drug encapsulated tubular membrane system. 11.The process of claim 3 wherein the drug suspension consists essentiallyof a drug suspended in a polymer solution.
 12. The process of claim 11wherein the polymer solution is selected from propylene glycol,polyethylene glycol having a molecular weight greater than about 400,about 1-12% by weight of a segmented polyurethane/urea indimethylacetamide, and about 1-5% by weight of polyvinyl alcohol inwater.
 13. The process of claim 3 wherein the temperature of thenon-solvent coagulant is in the range of about 60° to 180° C. toincrease the pore size in the tube polymer wall.
 14. The process ofclaim 3 wherein the extrusions of steps a. and b. and the non-solventcoagulant are at about the same temperature, said temperature in therange of about 15° to 180° C.
 15. A process for preparing a hollow tubedrug delivery system comprising:a. extruding a solution of about 15-40%by weight of a segmented polyurethane/urea derived from polyether glycolsoft segments in dimethylacetamide through an annular orifice to providea tubular membrane having a hollow core; b. simultaneously extrudinginto the hollow core of the tubular membrane a drug suspensionconsisting essentially of about 3-50% by weight of a drug suspended in apolymer solution selected from propylene glycol, polyethylene glycolhaving a number average molecular weight greater than about 400, about1-12% by weight of a segmented polyurethane/urea in dimethylacetamide,and about 1-5% by weight of polyvinyl alcohol in water, to provide adrug encapsulated tubular membrane system; c. passing the system after adraw-down into a polymer coagulation bath selected from water, an alkylalcohol of 1-3 carbon atoms and a mixture thereof, to provide a drugencapsulated porous hollow tube having an outside diameter of about0.5-10 millimeters; d. removing residual solvent from the drugencapsulated, porous hollow tube; and e. collecting the resulting tube.16. The process of claim 15 wherein the drug encapsulated tubularmembrane system is extruded downward into the coagulation bath throughan airgap to provide a gravity draw-down.
 17. The process of claim 16wherein residual solvent is removed by heating the drug encapsulated,porous hollow tube.
 18. The process of claim 17 wherein the tube iscollected on a wind-up roll.
 19. The process of claim 18 wherein thecollected tube is cut into lengths in the range of about 0.5 mm to about2 cm.
 20. The process of claim 19 wherein a plurality of the cut tubesare mixed with a suitable pharmaceutical carrier for oraladministration.
 21. The process of claim 16 wherein the extrusions ofsteps a. and b. and the coagulation bath are at about the sametemperature in the range of about 15° to 180° C.